SUBSTITUTION AND ELIMINATION REACTIONS OF ALKYL HALIDES SN

SUBSTITUTION AND ELIMINATION REACTIONS OF ALKYL HALIDES SN 1, SN 2, E 1 & E 2 REACTIONS 1

Reactions of Alkyl Halides (R-X): [SN 1, SN 2, E 1, & E 2 reactions] EN (F-C) = (4. 0 – 2. 5) = 1. 5 EN (Cl-C) = (3. 0 – 2. 5) = 0. 5 EN (Br-C) = (2. 8 – 2. 5) = 0. 3 EN (I-C) = (2. 5 – 2. 5) = 0. 0 The -carbon in an alkyl halide is electrophilic (electron accepting) for either or both of two reasons… a) the C to X (F, Cl, Br) bond is polar making carbon d+ b) X (Cl, Br, I) is a leaving group decreasing basicity, increasing stability The poorest leaving groups are the strongest bases. The best leaving groups are the weakest bases. increasing leaving ability 2

Reactions of Alkyl Halides (R-X): [SN 1, SN 2, E 1, & E 2 reactions] When a nucleophile (electron donor, e. g. , OH-) reacts with an alkyl halide, the halogen leaves as a halide There are two competing reactions of alkyl halides with nucleophiles…. 1) substitution 2) elimination The Nu: - replaces the halogen on the -carbon. The Nu: - removes an H+ from a -carbon & the halogen leaves forming an alkene. 3

2 nd Order Nucleophilic Substitution Reactions, i. e. , S N 2 reactions There are two kinds of substitution reactions, called SN 1 and SN 2. As well as two kinds of elimination reactions, called E 1 and E 2. Let’s study SN 2 reactions first. SN 2 stands for Substitution, Nucleophilic, bimolecular. Another word for bimolecular is ‘ 2 nd order’. q Bimolecular (or 2 nd order) means that the rate of an SN 2 reaction is directly proportional to the molar concentration of two reacting molecules, the alkyl halide ‘substrate’ and the nucleophile: Rate = k [RX] [Nu: -] (This is a rate equation and k is a constant). q The mechanism of an SN 2 reaction is the one shown on slide #2: q Note that the nucleophile must hit the back side of the -carbon. The nucleophile to C bond forms as the C to X bond breaks. No C+ intermediate forms. An example is shown on the next slide. 4

2 nd Order Nucleophilic Substitution Reactions, i. e. , S N 2 reactions The rate of an SN 2 reaction depends upon 4 factors: 1. The nature of the substrate (the alkyl halide) 2. The power of the nucleophile 3. The ability of the leaving group to leave 4. The nature of the solvent 1. Consider the nature of the substrate: q Unhindered alkyl halides, those in which the back side of the -carbon is not blocked, will react fastest in SN 2 reactions, that is: Me° >> 1° >> 2° >> 3° q While a methyl halides reacts quickly in SN 2 reactions, a 3° does not react. The back side of an -carbon in a 3° alkyl halide is completely blocked. 5

Effect of nature of substrate on rate of SN 2 reactions: methyl bromide isopropyl bromide t-butyl bromide SPACE FILLING MODELS SHOW ACTUAL SHAPES AND RELATIVE SIZES Back side of -C of a methyl halide is unhindered. Me°>> Back side of -C of a 1° alkyl halide is slightly hindered. 1° >> Back side of -C of a 2° alkyl halide is mostly hindered. 2° >> decreasing rate of SN 2 reactions Back side of -C of a 3° alkyl halide is completely blocked. 3° 6

Effect of the nucleophile on rate of SN 2 reactions: The -carbon in vinyl and aryl halides, as in 3° carbocations, is completely hindered and these alkyl halides do not undergo SN 2 reactions. vinyl bromide Nu: - bromobenzene Nu: - The overlapping p-orbitals that form the -bonds in vinyl and aryl halides completely block the access of a nucleophile to the back side of the -carbon. 7

Effect of nature substrate on rate of SN 2 reactions: 2. Consider the power of the nucleophile: q The better the nucleophile, the faster the rate of SN 2 reactions. q The table below show the relative power or various nucleophiles. q The best nucleophiles are the best electron donors. 8

Effect of nature of the leaving group on rate of SN 2 reactions: 3. Consider the nature of the leaving group: The leaving group usually has a negative charge q Groups which best stabilize a negative charge are the best leaving groups, i. e. , the weakest bases are stable as anions and are the best leaving groups. q Weak bases are readily identified. They have high p. Kb values. Increasing leaving ability q Iodine (-I) is a good leaving group because iodide (I -) is non basic. q The hydroxyl group (-OH) is a poor leaving group because hydroxide (OH -) is a strong base. 9

Effect of the solvent on rate of SN 2 reactions: 4. Consider the nature of the solvent: There are 3 classes of organic solvents: q Protic solvents, which contain –OH or –NH 2 groups. Protic solvents slow down SN 2 reactions. q Polar aprotic solvents like acetone, which contain strong dipoles but no –OH or –NH 2 groups. Polar aprotic solvents speed up SN 2 reactions. q Non polar solvents, e. g. , hydrocarbons. SN 2 reactions are relatively slow in non polar solvents. Protic solvents (e. g. , H 2 O, Me. OH, Et. OH, CH 3 COOH, etc. ) cluster around the Nu: - (solvate it) and lower its energy (stabilize it) and reduce its reactivity via H -bonding. A solvated nucleophile has difficulty hitting the -carbon. 10

Effect of the solvent on rate of SN 2 reactions: q Polar Aprotic Solvents solvate the cation counterion of the nucleophile but not the nucleophile. q Examples include acetonitrile (CH 3 CN), acetone (CH 3 COCH 3), dimethylformamide (DMF) [(CH 3)2 NC=OH], dimethyl sulfoxide, DMSO [(CH 3)2 SO], hexamethylphosphoramide, HMPA {[(CH 3)2 N]3 PO} and dimethylacetamide (DMA). 11

Effect of the solvent on rate of SN 2 reactions: Non polar solvents (benzene, carbon tetrachloride, hexane, etc. ) do not solvate or stabilize nucleophiles. q SN 2 reactions are relatively slow in non polar solvents similar to that in protic solvents. 12

1 st Order Nucleophilic Substitution Reactions, i. e. , S N 1 reactions q 3 alkyl halides are essentially inert to substitution by the S N 2 mechanism because of steric hindrance at the back side of the -carbon. q Despite this, 3 alkyl halides do undergo nucleophilic substitution reactions quite rapidly , but by a different mechanism, i. e. , the S N 1 mechanism. q SN 1 = Substitution, Nucleophilic, 1 st order (unimolecular). SN 1 reactions obey 1 st order kinetics, i. e. , Rate = k [RX]. q The rate depends upon the concentration of only 1 reactant, the alkyl halide-not the nucleophile q The order of reactivity of substrates for SN 1 reactions is the reverse of SN 2 3 R 3 C-Br > 2 R 2 HC-Br > 1 RH 2 C-Br > vinyl CH 2=CH-Br increasing rate of SN 1 reactions > phenyl -Br > Me° H 3 C-Br 13

Mechanism of SN 1 reactions The mechanism of an SN 1 reaction occurs in 2 steps: Reaction Steps … 1. the slower, rate-limiting dissociation of the alkyl halide forming a C+ intermediate 2. a rapid nucleophilic attack on the C+ Note that the nucleophile is not involved in the slower, rate-limiting step. 14

The Rate of SN 1 reactions The rate of an SN 1 reaction depends upon 3 factors: 1. The nature of the substrate (the alkyl halide) 2. The ability of the leaving group to leave 3. The nature of the solvent The rate is independent of the power of the nucleophile. 1. Consider the nature of the substrate: Highly substituted alkyl halides (substrates) form a more stable C+. increasing rate of SN 1 reactions 15

Stability of Carbocations Alkyl groups are weak electron donors. q They stabilize carbocations by donating electron density by induction (through bonds) q They stabilize carbocations by hyperconjugation (by partial overlap of the alkyl C-to-H bonds with the empty p-orbital of the carbocation). 16

Stability of Carbocations q Allyl and benzyl halides also react quickly by SN 1 reactions because their carbocations are unusually stable due to their resonance forms which delocalize charge over an extended system 17

Relative Stability of All Types of Carbocations Increasing C+ stability and rate of SN 1 reaction Note that 1° allylic and 1° benzylic C+’s are about as stable as 2°alkyl C+’s. Note that 2° allylic and 2° benzylic C+’s are about as stable as 3° alkyl C+’s. Note that 3° allylic and 3° benzlic C+’s are more stable than 3° alkyl C+’s Note that phenyl and vinyl C+’s are unstable. Phenyl and vinyl halides do not usually react by SN 1 or SN 2 reactions 18

Effect of nature of the leaving group on rate of SN 1 reactions: 2. Consider the nature of the leaving group: The nature of the leaving group has the same effect on both SN 1 and SN 2 reactions. The better the leaving group, the faster a C+ can form and hence the faster will be the SN 1 reaction. The leaving group usually has a negative charge q Groups which best stabilize a negative charge are the best leaving groups, i. e. , the weakest bases are stable as anions and are the best leaving groups. q Weak bases are readily identified. They have high p. Kb values. Increasing leaving ability q Iodine (-I) is a good leaving group because iodide (I -) is non basic. q The hydroxyl group (-OH) is a poor leaving group because hydroxide (OH -) is a strong base. 19

Effect of the solvent on rate of SN 1 reactions: 3. Consider the nature of the solvent: q For SN 1 reactions, the solvent affects the rate only if it influences the stability of the charged transition state, i. e. , the C+. The Nu: - is not involved in the rate determining step so solvent effects on the Nu: - do not affect the rate of SN 1 reactions. q Polar solvents, both protic and aprotic, will solvate and stabilize the charged transition state (C+ intermediate), lowering the activation energy and accelerating SN 1 reactions. q Nonpolar solvents do not lower the activation energy and thus make SN 1 reactions relatively slower The relative rates of an SN 1 reaction due to solvent effects are given (CH 3)3 C-Cl + ROH (CH 3)3 C-OR + HCl H 2 O 100, 000 20% Et. OH (aq) 14, 000 40% Et. OH (aq) 100 Et. OH 1 reaction rate increases with polarity of solvent 20

Effect of the solvent on rate of SN 1 reactions: q Solvent polarity is usually expressed by the “dielectric constant”, , which is a measure of the ability of a solvent to act as an electric insulator. q Polar solvents are good electric insulators because their dipoles surround associate with charged species. q Dielectric constants of some common solvents are given in the following table 21

Effect of the nucleophile on rate of SN 1 reactions: Consider the nature of the Nucleophile: q Recall again that the nature of the nucleophile has no effect on the rate of SN 1 reactions because the slowest (rate-determining) step of an SN 1 reaction is the dissociation of the leaving group and formation of the carbocation. q All carbocations are very good electrophiles (electron acceptors) and even weak nucleophiles, like H 2 O and methanol, will react quickly with them. q The two SN 1 reactions will proceed at essentially the same rate since the only difference is the nucleophile. 22

Elimination Reactions, E 1 and E 2: We have seen that alkyl halides may react with basic nucleophiles such as Na. OH via substitution reactions. Also recall our study of the preparation of alkenes. When a 2° or 3° alkyl halide is treated with a strong base such as Na. OH, dehydrohalogenation occurs producing an alkene – an elimination (E 2) reaction. bromocyclohexane + KOH cyclohexene (80 % yield) Substitution and elimination reactions are often in competition. We shall consider the determining factors after studying the mechanisms of elimination. 23

E 2 Reaction Mechanism There are 2 kinds of elimination reactions, E 1 and E 2 = Elimination, Bimolecular (2 nd order). Rate = k [RX] [Nu: -] q E 2 reactions occur when a 2° or 3° alkyl halide is treated with a strong base such as OH-, OR-, NH 2 -, H-, etc. The Nu: - removes an H+ from a -carbon and the halogen leaves forming an alkene. q All strong bases, like OH-, are good nucleophiles. In 2° and 3° alkyl halides the -carbon in the alkyl halide is hindered. In such cases, a strong base will ‘abstract’ (remove) a hydrogen ion (H+) from a -carbon, before it hits the -carbon. Thus strong bases cause elimination (E 2) in 2° and 3° alkyl halides and cause substitution (SN 2) in unhindered methyl° and 1° alkyl halides. 24

E 2 Reaction Mechanism In E 2 reactions, the Base to H bond formation, the C to H bond breaking, the C to C bond formation, and the C to Br bond breaking all occur simultaneously. No carbocation intermediate forms. Reactions in which several steps occur simultaneously are called ‘concerted’ reactions. Zaitsev’s Rule: Recall that in elimination of HX from alkenes, the more highly substituted (more stable) alkene product predominates. 25

E 2 Reactions are ‘antiperiplanar’ q E 2 reactions, do not always follow Zaitsev’s rule. q E 2 eliminations occur with anti-periplanar geometry, i. e. , periplanar means that all 4 reacting atoms - H, C, C, and X - all lie in the same plane. Anti means that H and X (the eliminated atoms) are on opposite sides of the molecules. q Look at the mechanism again and note the opposite side and same plane orientation of the mechanism: 26

Antiperiplanar E 2 Reactions in Cyclic Alkyl Halides q When E 2 reactions occur in open chain alkyl halides, the Zaitsev product is usually the major product. Single bonds can rotate to the proper alignment to allow the antiperiplanar elimination. q In cyclic structures, however, single bonds cannot rotate. We need to be mindful of the stereochemistry in cyclic alkyl halides undergoing E 2 reactions. See the following example. q Trans – 1 -chloro-2 -methylcyclopentane undergoes E 2 elimination with Na. OH. Draw and name the major product. 27

E 1 Reactions q Just as SN 2 reactions are analogous to E 2 reactions, so SN 1 reactions have an analog, E 1 reaction. q E 1 = Elimination, unimolecular (1 st order); Rate = k [RX] q E 1 eliminations, like SN 1 substitutions, begin with unimolecular dissociation, but the dissociation is followed by loss of a proton from the -carbon (attached to the C+) rather than by substitution. q E 1 and SN 1 normally occur in competition, whenever an alkyl halide is treated in a protic solvent with a nonbasic, poor nucleophile. q Note: The best E 1 substrates are also the best SN 1 substrates, and mixtures of products are usually obtained. 28

E 1 Reactions q As with E 2 reactions, E 1 reactions also produce the more highly substituted alkene (Zaitsev’s rule). However, unlike E 2 reactions where no C+ is produced, C+ rearrangements can occur in E 1 reactions. q e. g. , t-butyl chloride + H 2 O (in Et. OH) at 65 C t-butanol + 2 -methylpropene q In most unimolecular reactions, SN 1 is favored over E 1, especially at low temperature. Such reactions with mixed products are not often used in synthetic chemistry. q If the E 1 product is desired, it is better to use a strong base and force the E 2 reaction. q Note that increasing the strength of the nucleophile favors SN 1 over E 1. Can you postulate an explanation? 29

Predicting Reaction Mechanisms 1. Non basic, good nucleophiles, like Br- and I- will cause substitution not elimination. In 3° substrates, only SN 1 is possible. In Me° and 1° substrates, SN 2 is faster. For 2° substrates, the mechanism of substitution depends upon the solvent. 2. Strong bases, like OH- and OR-, are also good nucleophiles. Substitution and elimination compete. In 3° and 2° alkyl halides, E 2 is faster. In 1° and Me° alkyl halides, SN 2 occurs. 3. Weakly basic, weak nucleophiles, like H 2 O, Et. OH, CH 3 COOH, etc. , cannot react unless a C+ forms. This only occurs with 2° or 3° substrates. Once the C+ forms, both SN 1 and E 1 occur in competition. The substitution product is usually predominant. 4. High temperatures increase the yield of elimination product over substitution product. ( G = H –T S) Elimination produces more products than substitution, hence creates greater entropy (disorder). 5. Polar solvents, both protic and aprotic, like H 2 O and CH 3 CN, respectively, favor unimolecular reactions (SN 1 and E 1) by stabilizing the C+ intermediate. Polar aprotic solvents enhance bimolecular reactions (SN 2 and E 2) by activating the nucleophile. 30

Predicting Reaction Mechanisms SN 2 no reaction SN 2 E 2 (SN 2) no reaction SN 2 E 2 SN 1, E 1 SN 1 E 2 SN 1, E 1 Strong bulky bases like t-butoxide are hindered. They have difficulty hitting the -carbon in a 1° alkyl halide. As a result, they favor E 2 over S N 2 products. 31

Predicting Reaction Mechanisms The nucleophiles in the table are extremes. Some nucleophiles have basicity and nucleophilicity in between these extremes. The reaction mechanisms that they will predominate can be interpolated with good success. Predict the predominant reaction mechanisms the following table. v. gd. moderate 4. 7 fair weak 9 6. 0 / 7. 0 SN 2 SN 2 SN 2 E 2 SN 1 E 2 E 2 SN 1 HCl, HBr and HI are assumed to be in aqueous solution, a protic solvent. 32

Alkylation of Alkynides Recall the preparation of long alkynes. 1. A terminal alkyne (p. Ka = 25) is deprotonated with a very strong base… R-C C-H + Na. NH 2 R-C C: - Na+ + NH 3 2. An alkynide anion is a good Nu: - which can substitute (replace) halogen atoms in methyl or 1 alkyl halides producing longer terminal alkynes ¼ R-C C: - Na+ + CH 3 CH 2 -X R-C C-CH 2 CH 3 + Na. X q The reaction is straightforward with Me and 1 alkyl halides and proceeds via an SN 2 mechanism q Alkynide anions are also strong bases (p. Kb = -11) as well as good Nu: -’s, so E 2 competes with SN 2 for 2 and 3 alkyl halides CH 3(CH 2)3 C C: - Na+ + CH 3 -CH(Br)-CH 3 CH 3(CH 2)3 C CCH(CH 3)2 (7% SN 2) + CH 3(CH 2)3 C CH + CH 3 CH=CH 2 (93% E 2) 33

Preparation of Alkyl Halides from Alcohols Alkyl halides can be prepared from alcohols by reaction with HX, i. e. , the substitution of a halide on a protonated alcohol. Rapid. 3° C+ is stabilized by protic sovent (H 2 O) q OH- is a poor leaving group, i. e. , is not displaced directly by nucleophiles. Reaction in acid media protonates the OH group producing a better leaving group (H 2 O). 2 and 3 alcohols react by SN 1 but Me° and 1 alcohols react by SN 2. Very slow. Protic solvent inhibits the nucleophile. q Draw the mechanism of the reaction of isopropyl alcohol with HBr. q What products form if concentrated H 2 SO 4 is used in place of aq. HCl? 34

Preparation of Alkyl Halides from Alcohols Alternative to using hydrohalic acids (HCl, HBr, HI), alcohols can be converted to alkyl halides by reaction with PBr 3 which transforms OH- into a better leaving group allowing substitution (SN 2) to occur without rearrangement. 35

Preparation of Alkenes from Alkyl Halides We noted that 2° and 3° alkyl halides can be dehydrohalogenated with a strong base such as OH- producing an alkene. bromocyclohexane + KOH cyclohexene (80 % yield) Clearly, this is an E 2 reaction. q Predict the mechanism that occurs with a Me° or 1° alkyl halide. q Predict the products and mechanism that occur with isopropyl chloride and Na. OH 36

Summary of SN /Elimination Reactions Alkyl Halide Substrate Reactivity: 37

Summary of SN /Elimination Reactions Reactivity of Nucleophiles: Note that poor nucleophiles that are also weak bases (H 2 O, ROH, CH 3 COOH, etc. ) do not undergo any reaction unless a C+ is formed first. If a C+ can form (as with a 2º, 3º, any benzylic, or any allylic halides), then E 1 and S N 1 generally occur together. Leaving Group Activity: 38